Interactions between ligands and the cognate cell surface receptors are critical for a variety of biological processes including maintenance of cellular and organism homeostasis, development, and tumorigenesis. Many of these ligands can activate multiple independent pathways and the strength of the activation of different pathways can be modulated by the presence or absence of signals generated by other receptors, Hotamisligil, et al., Proc. Natl. Acad. Sci. USA 91: 4854-58 (1994); Kanety et al., J. Biol. Chem. 270: 23780-84 (1995); Luttrell et al., J. Biol. Chem. 272: 4637-44 (1997). Adaptor molecules may be critical in integrating multiple signaling cascades and in determining the cell type specific response to extracellular stimuli. These adaptor proteins have no apparent catalytic activity. Rather, they contain one or more domains that mediate protein-protein or protein-lipid interactions. The most common conserved interaction domains in these adaptor molecules are Src homology (SH2), SH)3, phosphotyrosine binding (PTB) and pleckstrin homology domains. [Reviewed in Pawson and Scott, Science 278: 2075-80 (1997)].
Signals generated by growth factors such as epidennal growth factor (EGF) or insulin growth factor-1 (IGF-1) through receptor tyrosine kinases (RTK) or by extracellular matrix components acting through the integrin receptors can induce cytoskeletal changes, Leventhal, et al., J. Biol. Chem. 272: 5214-18 (1997); Ojaniemi & Vuori, J. Biol. Chem. 272: 2443-47 (1996). There are also indications that RTKs can modulate integrin signals and vice versa, Doerr & Jones, J. Biol. Chem. 271: 2443-47 (1996); Jones et al., Proc. Natl. Acad. Sci. USA 93: 2482-87 (1996); Knight et al, J. Biol. Chem. 270: 10199-203 (1995); Matsumoto et al., Cancer Metas. Rev. 14: 205-17 (1995). However the details of how RTKs signal to the cytoskeletal components have not been fully resolved. Further, while some adaptor proteins have a limited pattern of expression [Liu & Roth, Proc. Natl. Acad. Sci. USA 92: 10287-91 (1995); Nakamura et al., Oncogene 13: 1111-21 (1996)], many are ubiquitously expressed [Araki et al., Diabetes 42: 1041-54 (1993); Frantz et al., J. Biol. Chem. 272: 2659-67 (1997)]. Thus, it is not clear how biologically relevant outputs are modulated as cells differentiate.